Vaccinations are the most successful and cost-effective interventions in modern medicine. An HIV vaccine could save millions of lives and would be the centerpiece of HIV eradication efforts. However, numerous challenges remain in developing a vaccine that shows substantial efficacy in humans. Infants are one group likely to benefit from vaccine protection by preventing the nearly 400,000 new Mother-to-child transmissions (MTCT) of HIV worldwide each year. Access to anti-retroviral treatment (ART) has dramatically reduced MTCT in developed countries; however postpartum HIV transmission persists at unacceptably high levels in resource-poor settings. The reasons for this include: formula feeding not being affordable or safe (water contamination), lack of compliance to taking the ART, benefits of breastfeeding for the health of the infant and access of ART to all pregnant HIV-infected woman and their babies. In South Africa (where we have an ongoing study to assess impact of BCG vaccination in infants), and many other developing countries, the two vaccines given at birth are Bacillus Calmette-Guerin (BCG) and Oral Polio Vaccine (OPV). While these vaccines have clear protective benefits against disseminated tuberculosis and polio infection, there is also a potential downside. The very immune activation that elicits these beneficial responses may simultaneously increase an infant's susceptibility to HIV. Sub-analyses from the STEP as well as subsequent macaque SIV vaccine studies have implicated specific vaccine-induced immune responses in promoting HIV infection in vaccine recipients. If vaccines with anti-HIV/SIV activity can enhance HIV/SIV susceptibility, it is critical to assess if current immunization strategies can impact HIV transmission in HIV-exposed infants. The goals of this proposal are to: 1) Assess the immunologic impact of administration of BCG and OPV vaccines on HIV/SIV target cell recruitment and activation in infant rhesus macaques, and 2) Define the mechanism of BCG/OPV-mediated immune modulation through ex-vivo stimulation of macaque and human cells. This proposal will test the hypothesis that early administration (within days of birth) of the neonatally-administered vaccines BCG/OPV increases the risk of oral SIV acquisition in infants. To address this hypothesis, the Sodora laboratory will draw on our extensive experience in innate immunology and macaque models of SIV-infection while collaborating with Dr. Deborah Fuller, an expert in vaccination studies and adaptive immunity, to develop a thorough understanding of BCG/OPV-induced immune responses. This proposal will define the impact of neonatal vaccinations on recruitment and activation of HIV/SIV target cells as well as SIV transmission, to provide insights into the role of BCG/OPV neonatal vaccinations on oral MTCT SIV/HIV transmission. The investigation of vaccines currently administered to HIV-exposed infants makes these studies particularly relevant for current clinical practice while also facilitating the development of an effective HIV vaccine with optimal safety for HIV-exposed individuals.